Antimicrobial resistance (AMR) looms among the greatest health and economic challenges of the 21st century. AMR causes more than 1 million deaths annually; by 2050, this number is forecast to double, piling over $1 trillion in additional costs onto stretched healthcare systems worldwide. Without urgent action, we risk a future where treating infectious diseases, chemotherapy, and surgery become impossible. Here, Dr William Smith, Dr Danna Gifford, and Dr Matthew Shepherd discuss how microbial evolution research informs long-term policy solutions to the AMR challenge.

• Principles from evolutionary biology can improve safeguarding of existing antimicrobials and accelerate development of new alternatives.
• To give the UK a global lead in infection treatment, policymakers should develop knowledge and data-sharing infrastructure for research into AMR evolution – in both the clinic, and clinical trials.
• Funding a flagship UK facility for development of biological antimicrobials would attract international pharmaceutical investment, and position the UK at the front of queue for next-generation medicines.

Antimicrobials are lynchpins of modern medicine, adding approximately 23 years to the average human lifespan. However, overuse has driven the rise of resistant microbes. As outlined in the UK’s latest 5-year National Action Plan, the government aims to safeguard current antimicrobials and develop new ones. Research at The University of Manchester has illustrated multiple ways that microbial evolution can inform robust, long-term AMR strategies. Incorporating these into policy would make treatments more effective immediately, and avoid future AMR crises.

Right drug, right person

Like cancer, AMR is often discussed as though it were a single phenomenon. However, our research highlights that resistance can emerge in multiple ways, depending on the patient and infection.

Sometimes, new resistance appears within a patient “de novo”, via natural mutations in microbes’ genes. Here, population size and the (highly variable) rate at which mutations occur are vital predictors of resistance emergence; the presence of “hypermutator” strains can dramatically increase the likelihood of single- or multi-drug resistance.

In other cases, however, pre-existing resistance is present before treatment even begins. Rare types of resistance can go unnoticed by conventional susceptibility testing, and might migrate in from elsewhere in a patient’s body during treatment. Crucially, knowledge of within-patient evolution offers the opportunity to personalise therapy to individuals’ needs, making treatments more likely to succeed while reducing selection for further resistance.

For instance: where de novo resistance dominates, targeting hypermutator strains and minimising the population of disease-causing microbes both make strategic sense. Where pre-existing resistance dominates, strategies need to instead prioritise deeper sampling of infections and limiting migration between body sites. In this case, it is also vital to consider a patient’s treatment history: repeatedly using the same antibiotic from past treatments risks spreading resistance, as microbes resistant to this drug are likely already present within the patient.

A better understanding of within-patient resistance evolution would enable more effective and robust use of antimicrobials. Despite its promise, however, within-patient evolution is poorly understood and clinically implemented. Government support is needed to foster collaboration, share resources, and build biobanks of infection data. The Government Office for Science has a role in facilitating and coordinating this, alongside the departments of Health and Social Care, and Science, Innovation and Technology.

Incentivising development of resistance-durable antimicrobials

Safeguarding existing antimicrobials is vital, as is developing alternatives. Our research shows not all antimicrobials are created equal: some, such as nitrofurantoin, are intrinsically more robust to resistance evolution. However, selective approaches to prioritise drugs to which resistance is less likely to exist – or evolve – are undermined by a lack of testing. In most cases, resistance evolution is not assessed as part of clinical trials for new antimicrobials. Instead, drug developers routinely screen for resistance at the discovery phase, using simplistic lab tests that fail to capture how likely mutations are to emerge and spread within real patients.

Policy mandating resistance monitoring at the clinical trial stage would enable realistic forecasting of resistance, and facilitate the design of more effective and durable treatment plans. While making trials more expensive initially, it would also create opportunities to reward companies fielding resistance-durable therapeutics: for instance, by offering enhanced market entry awards, or reducing the efficacy threshold required in a trial. It also offers opportunities to “rescue” antimicrobials that fail because of resistance evolution – such candidates may still be useful if combined with other drugs that limit resistance evolution.

This approach would prevent unnecessary loss of valuable compounds from the pipeline, and incentivise and reward novel, durable antimicrobials, making the UK a more attractive environment in which to conduct clinical trials – one of the aims of the government’s Health Mission.

Biological antimicrobials as options to counter resistance evolution

No new antibiotic classes have been approved as therapeutics in over 30 years. Most are derived from natural compounds—but nature offers more. Many organisms have evolved their own means to target and kill bacteria, resulting in a diverse array of biological antimicrobials that could be harnessed as therapeutics.

Though there are no ‘silver bullets’ in the fight against AMR, biological antimicrobials offer two key advantages over conventional drugs: variety and robustness. Antimicrobial compounds can be modified and rationally engineered to tune their properties – for instance, by altering the microbe(s) or virulence factors they target. Typically, they also benefit from high specificity compared with conventional drugs; this helps to avoid both selecting for resistance among non-target microbes, and collateral damage to the helpful microbes that live in every human body.

While multiple classes of biological antimicrobials have shown promise in preclinical testing (such as phages or bacteriocins), there remain practical barriers to their adoption. Compared with conventional drugs, the UK lacks infrastructure and expertise in making these therapeutics, while in countries such as Belgium and Slovenia these are already well-established. This creates a Catch-22 situation: pharmaceutical giants require clinical trials before they will invest in manufacturing, but clinical trials cannot proceed until antimicrobials have been manufactured to requisite standards.

Infrastructure to make, test and regulate these antimicrobials has the potential to unlock a new era in pharmaceutical discovery, putting the UK at the front of the queue for new medicines. Government investment in a flagship UK facility for biological antimicrobial engineering would be transformative in breaking the deadlock, supercharging the booming UK biotechnology industry and attracting major investment from the pharmaceuticals sector. As noted in the Spending Review, every £1 spent on research and development generates up to £7 in returns to the economy, supporting the Growth Mission.

The UK has the research expertise to take a lead on this – matching this with robust policy and investment will not only generate economic returns, but ensure the NHS is delivering the latest and most effective treatments for patients.